Physiologically active compounds and a method of making the same



Patented Feb. 12, 1946 PHYSIOLOGICALLY ACTIVE COMPOUNDS AND A METHOD OFMAKING THE SAME Arthur Serini, Berlin N. 65, and Konrad Steinruck,Berlin-Tegel, Germany, assignors to Schering Corporation, Bloomfield NewJersey N. J'., a corporation of v No Drawing. Application August 6,1938, Serial No. 223,530. In Germany August 7, 1937 13 Claims.101.260-4791 This invention relates to physiologically active compoundsand more particularly to compounds possessing an oestrogenic activity,and a method of making the same. I

It is already known that fsynthetic oestrogenic compounds" can be madein a rather complicated manner by synthesizing henanthrene derivatives;compare, for instance Cook and Dodds in Oppenheimer, Handbuch derBiochemie der Menschen und Tiere 2 edition, volume 3, pages 774-775(1936). It is furthermore known that polymerisation products ofunsaturated phenols. for instance, of p-propenylphenol possess a certainoestrogenic activity; compare, for instance, Dodds and Lawson Nature1937, number 3519 page 627 and number 3529, page 1068. The activity ofthese compounds; however, as has been found by experiment, is so low,namely 100 mg.

for 1 rat unit, that these products cannot be employed therapeutically.

Now, it has been found that new products of wherein R represents analkyl group with more a considerably higher oestrogenic activity areobtained by subjecting propenylphenols, especially p-propenylphenol, orpropenylphenols in statu' nascendi, as obtained, for instance, bysaponification of their ethers such as anethol by means of Grignardreagent, to the action of metalloorganic compounds, especially of alkylmagnesium halides and isolating from the reaction mixture theoestrogenic compounds. A further increase of the activity of compoundsobtained in this manner or by any other method is caused by esterifyingthe same. The best purification of the esters is achieved onfractionally distilling the esterlfied product, preferably in a highvacuum. As alkyl magnesium halides those with various alkyl radicals maybe employed. Ethyl magnesium halide, however, has proved to be the bestmeans yielding the most active products. As stated above in connectionwith the purification of the esters, the separation of the oestrogeniccompounds from inactive reaction products is preferably carried out byfractional distillation in a high vacuum. However, other chemical orphysical purification methods, for instance, fractional crystallisation,sublimation and v the like may be used likewise.

The constitution of the new compounds is not yet known. Most probablypolymerisation takes place. It is, however, also possible that besidespolymerisation of two mols of the propenylphenols at the same time anaddition of one or two alkyl groups at the double bond of the propyleneresidue may occur. Hence, the constitution of the new compoundsmaybe'given as follows:

i of absolute ether.

than five C-atoms, especially with more than seven C-atoms, while R.represents a hydroxyl group or an ester group. i

The invention may. be illustrated by the following examples without,however, same tothem.

Example 1 hour on the water bath'the ether is distilled off from themixture in an oil bath whereafter the temperature is increased for 1hour to 160 C. The residue is then decomposed by means of ice whileadding 3 n. sulphuric acid, extracted with ether, the ether is distilledoff, and the remaining product distilled in a high vacuum at 140- 160 C.and 0.001 mm. The product distilled over, about 8 g., represents aviscous dark-coloured oil having an activity of 2500 'y for 1 rat unit.On repeated fractional distillation in a high vacuum a. fraction isobtained boiling between 140-150 C. at 0.001 mm. that yields onsolidifying about mg. of a glassy product having an activity of 30 'yfor 1 rat unit.

'These 60 mg. are heated with 1.5 cc. of acetic acid anhydride forseveral hours under reflux whereupon the acetic acid anhydride isdistilled off in a vacuum. The remaining viscous oil is then distilledin a high vacuum between 150- 170 C. at 0.001 mm. The distillate isdissolved in a little methanol and the solution is cooled to 20 C.Thereby small crystals separate having a melting point of 186 C. theactivity of which on subcutaneous application is found at 5-10 and orperoral application at 407 for 1 rat unit. Such a compound in co t'fastto the known follicle hormone shows an excellent peroral activity; for,the follicle hormone has only a peroral activity of Example 2 A Grignardsolution is made from 2.43 g. of magnesium and 15.6 g. of ethyl iodidein .100 cc. Thereupon the ether is distilled off whereby the temperatureis increased to G. Then 15.7 g. of anethol are added at once and thereaction solution is heated up to 5 C. Thereby the reaction mixturefoams clue to the development of gas and finally solidifies.

limiting the '15.? g. of anethol are addedat once-"toitheresi It is thendecomposed by means of ice and dilute. sulphuric acid. The viscous oilobtained thereby is extracted with ether and the ether solution shakenwith dilute sodium hydroxide solution in order to remove the phenolicproducts. On acid- I ifying the alkaline solution phenolic products areliberated and extracted with ether. After distilling oil the ether theresidue is rectified in a high vacuum. The amount distilling over be- Itween 1l0-120 C. that represents mostly ppropenyl phenol is separatedand the product.

distilling over between 120-180 C. at 0.001 mm. is again distilled in ahigh vacuum. The fraction distilling over between 140 150 C. 8170.001.

mm. yields on solidification the same glassy product as is obtainedaccordingto Example 1.

having a meltin point of 186 C. and the same physiological activity asthe acetate compound ofExamplel. v

- Eaiample 3 A Grignard solution is made from-2.43"; of, magnesium and1'7 g. of propyl iodide in 100 cc.

of absolute ether. Afterdistillingoil, that ether v whereby thetemperature is increasedrto: 13090.,

due. whereupon the; reaction mixture is: heated.

up to 11' Q -.Fam ek 3 due-t9 the development ofgas.f-lhs'olidifiellreactionj mixture 'is then decomposed by the addition'oi' ice and dilute sulphuric' acid. The separated vis- 1 cous oil isextracted'withether and the phenolic products are removed fromthe-ethereal solution a by shaking; the same with dilute 1 sodium'hydroxide solution. ..The alkaline solution; is then acidified andextracted with; ether. 9.3"gh'o1' thej' residue obtained afterdistilling off the ether are purifiedby rectificationina high vacuum.-"'I'h e portion distilling over betw'een 1 10-120 C. and .consistingmostly offppropenyl ph'enol isjiseparated, and the 4.5g." fof. .theportiondist'illing b'etween 209 0. atiillodl mm. are again dis-' tilledin a high vacuu i., The fractiondistilling between 150- 170 c. at Q.0Q1mm.jf Orms' after solidification a similar-glass-like product'to thatobtained according to Example; 1. won acetyletion and high vacuumdistillation-at0.001 mm. amain fraction is obtained distilling over between -l80 C. Upon trituratin'gvthe' same 59 with a little methanol andcooling the solution to a low temperature, small white needles areobtained having a melting point of C. Their physiological activityamounts..to"5,10 'y for 1 rat 0.001 mm, shows an activity of 200 'y for1 rat unit. 'Onacetylation and further high vacuum dis- "tillation' aphysiologically highly active acetate is obtained from said phenoliccompound. 5

Erample 5 v The procedure is the same as described in Example 4.

On benzoylation and high vacuum distillation 70 Va. benzoate is obtainedhaving a high physiological activity;

. Example 6 A Grignard solution is made from 4.85 g. of magnesium and 33g. of ethyl iodide in 0 cc. 75

. '20 obtained therefrom.

tion the phenolic components are removed by v shaking with dilute sodiumhydroxide solution.

The alkaline solution is then acidfied and extracted with ether. Afterdistilling off the ether the residue is rectified in a high vacuum. The

fraction distilling over at 220 C. and 0.001 mm.

On acetylation an acetate compound is obtained contains a rat unit in200 'y. l

On acetylation and further high vacuum distillation a physiologicallyhighly active acetate is Example 7 "The procedure-isthe same asdescribed in: Ex; 1

ample swing the exception that in the place of ethyl-iodide. methyliodideis used and in the place-of iso-eugenol methyl ether 20g. ofbutenyl anisolareused. The distillate obtained at 220 C.

" and"0.001 mm. contains a rat unit in 500 v.

' Onreaction-with propionic' acid anhydride and. furtherhigh vacuumdistillation a physiologically highly active propio'nate is obtainedtherefrom.

, .Example .8 The procedure is the same as described in Example. 6.with'the exception that in the place of f isoeugenol methyl ether 20 g.of vinyl, anisol are used. The distillate obtained betweeh180-210 C. at0.00-1mm. has an activity of 200 'y for 1 rat unit; 3

- n acetylation and further high vacuum distillation a physiologicallyhighly active acetate is obtained therefrom. I I I The terms phenolscontaining an unsaturated side chain as well as propenyl phenols as usedin'the specification and claims include all phenolic compounds which aresubstituted by an alkylene radical i. e. an aliphatic or alicyclichydrocarbon radical having at least one double bond in their molecule.

Of course, many changes and variations may 1 v be made in the reactionconditions, the tempera- .ture employed, the concentration of thecompounds, the isolation and the purification methods used and so forthin accordance with the principles set forth herein and in the claimsannexed hereto. I

What we claim is:

l. A method for making physiologically active compounds comprisingsubjecting a member of the class consisting of free and etherifledphenols 7 containing an unsaturated side chain to th action 01 anorgano-metal compound in which the metal is directly joined to a carbonatom and isolating from the reaction mixture the oestro enie product. i

2. A method for making physiologically active compounds comprisingsubjecting a member 01' the class consisting of free and etherifiedpropenyl P enols to the action of an organo-metal compound in which themetal is directly joined to a carbon atom, and isolating from thereaction mixture the oestrogenic product.

3. A method for making physiologically active compounds comprisingsubjecting p-propenylphenol to the action oi an organo metal com-,

pound in which the metal is directly joined to a carbon atom, andisolating from the reaction mixture the oestrogenic product.

4. A method according to claim 1 wherein a phenol containing anunsaturated side chain, in statu nascendi is used as starting material.

5. A method according to claim 1 wherein a phenol containing anunsaturated side chain, in statu nascendi as Obtained on hydrolysis ofits phenolic derivatives is used as starting material.

6. A method according to claim 1 wherein ethyl magnesium-iodide is usedas a-reaction component.

'7. A method according to claim 1 wherein the oestrogenic compound isseparated from the reaction mixture by fractional distillation.

8. A method according to claim 1 wherein the oestrogenic compounds areseparated from the reaction mixture by fractional distillation in a highvacuum.

9. A method for making physiologically active compounds comprisingesterifying compounds as may be obtained according to claim 1 to form acarboxylic ester, and separating from the esterification mixture theresulting esters;

10. A method for making physiologically active compounds comprisingtreating with acetylating agents a compound obtained according to claim1 and separating the acetate ester from the acetylation mixture.

11. A method for making physiologically active compounds comprisingesterifying a compound obtained according to claim 1, to form a carboxlic ester separating the ester from the esteriflcation mixture andpurifying the ester b tractional distillation in a high vacuum.

12. The estrogenic product produced by heating a hydroxybenzene havingan unsaturated side chain of three carbon atoms in the presence of aGrignard reagent, followed by conversion into a carboxylic acid ester.

13. A method according to claim 1 wherein the reaction takes place inthe presence of a. Grig nard reagent.

ARTHUR SERINI. KONRAD STEINRUCK.

